Evolutionary theory says mutations are blind and occur randomly. But in the controversial phenomenon of adaptive mutation, cells can peek under the blindfold, increasing their mutation rate in response to stress.
Scientists at Winship Cancer Institute, Emory University have observed that an apparent “back channel” for genetic information called retromutagenesis can encourage adaptive mutation to take place in bacteria.
The results were published Tuesday, August 25 in PLOS Genetics.
“This mechanism may explain how bacteria develop resistance to some types of antibiotics under selective pressure, as well as how mutations in cancer cells enable their growth or resistance to chemotherapy drugs,” says senior author Paul Doetsch, PhD.
Doetsch is professor of biochemistry, radiation oncology and hematology and medical oncology at Emory University School of Medicine and associate director of basic research at Winship Cancer Institute. The first author of the paper is Genetics and Molecular Biology graduate student Jordan Morreall, PhD, who defended his thesis in April.
Retromutagenesis resolves the puzzle: if cells aren’t growing because they’re under stress, which means their DNA isn’t being copied, how do the new mutants appear?
The answer: a mutation appears in the RNA first. Read more
As a followup to yesterday’s post on following troublemaker cells in patients with lupus, we’d like to highlight a recent paper in Blood that takes a similar approach to studying how the immune system comes back after bone marrow/blood stem cell transplant.
Leslie Kean, MD, PhD
The paper’s findings have implications for making this type of transplant safer and preventing graft-versus-host disease. In a bone marrow/blood stem cell transplant, to fight cancer, doctors are essentially clearing out someone’s immune system and then “planting” a new one with the help of a donor. What this paper shows is how much CMV (cytomegalovirus) distorts the new immune system.
CMV is often thought of as harmless — most adults in the United States have been infected with CMV by age 40 and don’t get sick because of it. But in this situation, CMV’s emergence from the shadows forces some of the new T cells to multiply, dominating the immune system so much that it creates gaps in the rest of the T cell repertoire, which can compromise protective immunity. Other seemingly innocuous viruses like BK cause trouble in immunosuppressed patients after kidney transplant.
The senior author, Leslie Kean, moved from Emory to Seattle Children’s Hospital in 2013, and her team began these studies here in 2010 (a host of Emory/Winship hematologists and immunologists are co-authors). This paper is sort of a mirror image of the Nature Immunology paper on lupus because it also uses next-generation sequencing to follow immune cells with DNA rearrangements — in this case, T cells. Read more
A mutation found in most melanomas rewires cancer cells’ metabolism, making them dependent on a ketogenesis enzyme, researchers at Winship Cancer Institute of Emory University have discovered.
The V600E mutation in the gene B-raf is present in most melanomas, in some cases of colon and thyroid cancer, and in the hairy cell form of leukemia. Existing drugs such as vemurafenib target the V600E mutation — the finding points to potential alternatives or possible strategies for countering resistance. It may also explain why the V600E mutation in particular is so common in melanomas.
Researchers led by Jing Chen and Sumin Kang have found that by promoting ketogenesis, the V600E mutation stimulates production of a chemical, acetoacetate, which amplifies the mutation’s growth-promoting effects. (A feedback mechanism! Screech!)
The results were published Thursday, July 2 in Molecular Cell.
More on this paper here.
Part of the new Winship magazine feature on prostate cancer focuses on a PET imaging probe called FACBC, which was developed by radiologists at Emory. 18F-FACBC (anti-1-amino-3-[18F]fluorocyclobutane-1-carboxylic acid, also called “fluciclovine”) has a lengthening track record in detecting recurrent prostate cancer.
Structure of FACBC, from patent application.
Usually in PET imaging, radioactive glucose is injected into the body, and since cancer cells have a sweet tooth, they take up a lot of the radioactive tracer. But plenty of the tracer also appears in the urine, complicating prostate cancer detection efforts, since the prostate is so close to the bladder. In contrast, FACBC is readily taken up by prostate cancer cells, but doesn’t appear as much in urine.
Because of space considerations, we did not include David Schuster’s description of how FACBC’s utility in prostate was first discovered. Several years ago, he and Mark Goodman had begun investigating the probe’s potential in imaging brain tumors and kidney tumors, and used it with a patient with a large renal mass and many enlarged lymph nodes, as described in the radiology newsletter Aunt Minnie. Read more
The big news from the recent American Society of Clinical Oncology meeting has been largely about immunotherapy drugs, also known as checkpoint inhibitors. These drugs have been shown to be effective in prolonging life in patients with some types of cancer, such as lung cancer and melanoma, but not others, such as colorectal and prostate cancer.
Lab Land asked oncologist Bradley Carthon and immunology researcher Haydn Kissick why. Both Carthon’s clinical work and Kissick’s lab research on prostate cancer are featured in the new issue of Winship magazine, but the prostate feature just touches on checkpoint inhibitors briefly.
Carthon says the reason checkpoint inhibitors haven’t moved the needle with prostate cancer is “likely due to the absence of infiltration of the prostatic tissue by tumor-associated lymphocytes.”
Checkpoint inhibitors are supposed to unleash the immune system, but if the immune cells aren’t in contact with the cancer cells so that the drugs can spur them into action, they won’t help much. Carthon says: “The answer may be to ‘prime’ the prostate with an agent, then introduce the checkpoint inhibitors.” Read more
The PSA (prostate specific antigen) blood test has been criticized for years for driving men to seek biopsies and then definitive treatment for slow-growing cancers that may not pose a danger.
At the recent AUA meeting in New Orleans, urologist Martin Sanda presented results from research on tests that could allow the urology field to move beyond the PSA test as it is now. Winship magazine’s cover story has more on this topic.
Martin Sanda, MD is director of Winship Cancer Institute’s Prostate Cancer Program and chair of urology at Emory University School of Medicine
Right now, only about a sixth of men who have a biopsy based on the results of a PSA test have something that doctors agree should be called a cancer (a tumor with a Gleason score of seven or higher).
Sanda described studies on a urine test that could double that specificity, possibly eliminating unnecessary biopsies for many men. Read more
Emory dermatologist Jack Arbiser discovered the anti-angiogenic properties of honokiol, a compound derived from magnolia cones, more than a decade ago. Since then, honokiol has been found to have anti-inflammatory, anti-oxidant and anticancer properties.
A paper published Tuesday in Nature Communications from researchers at the University of Chicago shows that honokiol inhibits the mitochondrial enzyme Sirt3, which has connections to longevity. Manesh Gupta and colleagues demonstrate that honokiol can block cardiac hypertrophy in mice, a finding with possible relevance for the treatment of heart failure.
Sirt3 has been linked both genetically to human life span, and until now, the only way to increase levels of Sirt3 was old-fashioned calorie restriction and/or endurance exercise.
The authors write: It is believed that Sirt3 does not play a role in embryonic development, but rather it fine tunes the activity of mitochondrial substrates by lysine deacetylation to protect cells from stress… To the best of our knowledge, this is the first report describing a pharmacological activator of Sirt3.
Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory and Winship Cancer Institute researchers have found.
The results were published this week in the journal PLOS Pathogens.
The findings suggest imatinib, known commercially as Gleevec, or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.
“We think that low doses of imatinib are mimicking ‘emergency hematopoiesis,’ a normal early response to infection,” says senior author Daniel Kalman, PhD, associate professor of pathology and laboratory medicine at Emory University School of Medicine.
Imatinib, is an example of a “targeted therapy” against certain types of cancer. It blocks tyrosine kinase enzymes, which are dysregulated in cancers such as chronic myelogenous leukemia and gastrointestinal stromal tumors.
Imatinib also inhibits normal forms of these enzymes that are found in healthy cells. Several pathogens – both bacteria and viruses – exploit these enzymes as they transit into, through, or out of human cells. Researchers have previously found that imatinib or related drugs can inhibit infection of cells by pathogens that are very different from each other, including tuberculosis bacteria and Ebola virus. Read more
MicroRNAs have emerged as important master regulators in cells, since each one can shut down several target genes. Riding on top of the master regulators is Drosha, the RNA-cutting enzyme that initiates microRNA processing in the nucleus. Drosha and its relative Dicer have been attracting attention in cancer biology, because they are thought to be behind a phenomenon where cancerous cells can “infect” their healthy neighbors via tiny membrane-clothed packets called exosomes.
At Emory, pharmacologist Zixu Mao and colleagues recently published in Molecular Cell their findings that Drosha is regulated by stress (experimentally: heat or peroxide) through p38 MAP kinase.
Although we mention relevance to cancer above, this is one of those basic cell biology findings that may have applicability to several areas of medicine. Alterations in miRNA processing have been linked to neurodegenerative disease (Fragile X-associated tremor/ataxia syndrome, for one example). MicroRNA-packed exosomes are also being studied by biomedical engineers as potential therapeutic tools in regenerative medicine, so knowing what cellular stress does to miRNA production could be useful. Read more